Women and autoimmune diseases

Abstract

Autoimmune diseases affect approximately 8% of the population, 78% of whom are women. The reasons for the high prevalence in women are unknown, but circumstantial evidence links autoimmune diseases with preceding infections. Animal models of autoimmune diseases have shown that infections can induce autoimmune disease. For example, coxsackievirus B3 (CB3) infection of susceptible mice results in inflammation of the heart (myocarditis) that resembles myocarditis in humans. The same disease can be induced by injecting mice with heart proteins mixed with adjuvant(s), which indicates that an active infection is not necessary for the development of autoimmune disease. We have found that CB3 triggers autoimmune disease in susceptible mice by stimulating elevated levels of proinflammatory cytokines from mast cells during the innate immune response. Sex hormones may further amplify this hyperimmune response to infection in susceptible persons, which leads to an increased prevalence of autoimmune diseases in women.

Figure 1

Major autoimmune diseases, comparing the incidence of disease in women (white bar) to the incidence in men (black bar) by percentage. Modified from (5).

Figure 2

nfections occur before the onset of symptoms of autoimmune disease, making links to specific causative agents difficult. When a person is first infected (day 0), usually no symptoms are apparent. Signs and symptoms of autoimmune disease are clearly present and easily confirmed by physicians during the chronic stage of autoimmunity. However, the infection has been cleared by this time, making it difficult to establish that an infection caused the autoimmune disease. Modified from (16).

Figure 3

Proinflammatory cytokines are increased in the hearts of susceptible mice during acute myocarditis. Susceptible BALB/c mice were compared to resistant C57BL/6 mice for the level of cytokines tumor necrosis factor (TNF)-α (A) and interleukin (IL)-1β (B) in heart homogenates 12 days after CB3 infection. Data are represented as the mean ± standard error of the mean. *p < 0.05.

Figure 4

Proinflammatory cytokines are increased in the hearts of susceptible mice during the innate immune response. Susceptible BALB/c mice were compared to resistant C57BL/6 mice for the level tumor necrosis factor (TNF)-α (A), interleukin (IL)-1β (B), and IL-4 (C) cytokines in heart homogenates 6 and 12 hours after CB3 infection. Data are represented as the mean ± standard error of the mean. *p < 0.05; ***p < 0.001. Modified from (33).

Figure 5

Mast cells are increased in the spleens of susceptible BALB/c mice 6 hours after CB3 infection. Data are represented as the mean ± standard error of the mean. ***p < 0.001. Modified from (33).

Figure 6

Sex hormones increase myocarditis in female and male mice by increasing interleukin (IL)-1β and tumor necrosis factor (TNF)-α levels in the heart. Susceptible female (A,C) and male (B,D) BALB/c mice underwent gonadectomy (Fem op/Male op) and were compared to sham-operated controls (Fem sham/Male sham) for the level of myocarditis (% inflammation) and cytokines (pg/g) in the heart after CB3 infection. CB3 myocarditis was assessed for (A) female mice and (B) male mice after the operation. Data are represented as the mean ± standard error of the mean. *p < 0.05.